Cyclopentano-phenanthrene compounds and method of producing same



r tested Nov. '5, 1940 UNITED STATES COM- ;POJJNDS AND Mansion on raonuome "SAME Erwin Schwenk, Montclair, N. J., and Bradley Whitman, New York, N. Y., assignors to Schering Corporation, Bloomfield, N. J., a corpora-'- tion of New Jersey No Drawing. Application May 6, 1936 Serial No. 78,222 i 2'! Claims.

The present invention relates to the production' of compounds having the cyclopentanopolyhydro-phenanthrene structure in their molecules by the decomposition, or more specifically the cracking, of compounds of similar molecular structure, but having a substituting alkyl or aralkyl group containing a methylene group, whereby such substituting group is split oi! in 1 whole or in part.

This application is a continuation-in-part of our copending application Serial No. 751,578, filed November 5, 1934, which issued on May 4, 1937, as Patent No. 2,078,978.

According to the present invention, cyclopentano polyhydro phenanthrene compounds, such as sterolic compounds, of the general formula Y z B wherein X is H, HH, 0, OH, or a group which on hydrolysis is converted into a hydroxyl group, Y and Z are hydrogen or a methyl group, and R is a substituting group which includes an aliphatic chain of a plurality of carbon atoms and containing a methylene group, and also the compounds which are derivable from the hydroxy compounds by splitting oif water formed by the OH group and the neighboring hydrogen, that is, the anhydro compounds, and wherein the cyclopentano polyhydro phenanthrene nucleus and the group R are saturated or unsaturated, are subjected to a partial cracking to remove all or part of the R group while the nucleus itself remains unbroken. The invention thus contemplates the cracking also of compounds containing the cyclopentano-polyhydro-phenanthrene nucleus f and having the formula CH: CH: R;

- converted into a hydroxyl group.

We have found that it is possible to split off the side chain of cyclopentano-phenanthrene compounds, particularly sterolic compounds, including cholestene, cholestane, dihydrocholesterol, tetrahydrostigmasterol, dihydrositosterol,

drocholesterol-methylether,

tetrahydroergosterol, coprosterol, epi-dihydrocholesterol and their derivatives, like cholestanone, cholestenone, the organic and inorganic esters and ethers of these compounds, like dlhy- ,bis-dihydrocholesterylether, their acetals and the like, by a process of overheating or superheating these compounds alone or in the presence of diluents or catalysts to a cracking temperature. vAs diluents, substances of'an inert character like hydrocarbons may be used, provided that the boiling point is not substantially lower than the decomposition temperature of the sterol compound or its derivative. As catalysts, finely divided metals or salts may be used, such as finely divided nickel, palladium, platinum and other metals or mixtures thereof, cuprous chloride, aluminum chloride and other known catalysts employed in cracking operations. The reaction is carried out under such conditions that the side chain is split ofl in the form of a hydrocarbon, such as iso-octane or isooctene, the following equations showing the probable course of the reaction in the case of, for example, cholestanone, the symbol R representing the substituted and at least partially hydroge- The yields of the cracking reaction are remarkably high, sometimes being quantitative.

We have found that the compounds which remain after the splitting reaction is performed are oily or crystalline substances and are suitable for the preparation of pharmaceutical substances of 2 aaaome the cyciopentano-phenanthrene type, and particularly of hormones and substances having a physiological activity similar to that of hormones; and in a further development of the invention I these compounds are treated to introduce desirable substituting groups into the molecule.

I The cracking is accomplished by heating the sterol compound at a temperature considerably above its melting pointand even at or near its 1 boiling point. The temperature range of 280 400 C. will be found to be suitable for most compounds. The time of reaction will depend on the temperature and on the nature of the compound being heated, but the end point of the reaction can generally be determined by weighing the distilled by-product or by-products. The reaction is preferably carried on under such conditions that the split-oil. side chain is distilled off,

so so that the equilibrium is disturbed and the reaction proceeds in the desired direction. Sometimes it is good to use a low vacuum for carrying on the split products, or a stream of inert gas may be used for the same purpose.

8 By superheating or partial cracking is to be understood heating to a temperature at which the aliphatic side chain is split on, thetemperature being maintained within a relatively narrow range above this minimum temperature, and in 80 no event is the temperature to be raised to such a point that cracking of the nucleus occurs to any considerable extent.

The invention will be described in greater detail with the aid of the following examples which a are presented by way of illustration only and not as indicating the limits of the invention:

Example 1 20 g. of cholestene (obtained from dihydrocholesterol by splitting oil water with 80% sulfuric acid and recrystallized, and having a M. P.

of 72 74 C.) are superheated so that a mixture of iso-octane and iso-octene is slowly distilled oil. The residue is dissolved in acetic acid and a 1% of silver sulfate (based on the weight of the residue) is added. To this mixture 10 g. of hydrogenperoxide containing 30 vol. per cent. of hydrogenperoxide are added drop by drop under 50 cooling from the outside. The reaction mixture is stirred'vigorously and then left standing for 15 hours at room temperature. A mixture of oxidation products is obtained, which is taken up with ether, the ether solution washed with water 55 and soda solution to remove acetic acid, again with water and then the ether is removed by disstillation. The residue is heated gently with a solution of a mineral acid, as for instance, alcoholic sulfuric acid to rearrange the oxides that are obtained to the keto form. mixture is taken up with ether, this solution washed with water, soda solution and water again and dried. The residue after evaporation is dis- 65 solved in times its weight of alcohol and precipitated with semicarbazide solution, which gives y 70 Example 2 10 g. dihydrocholesterol-methyl-ether are heated to a cracking temperature as described in Example 1. A similar mixture of iso-octane and 7 iso-ocetene is obtained. The residue, after standing for several days, solidifies in white crystals. Analysis reveals them to be a mixture of 3- methoxy-androstane and 3-methoxy-androstene, which isconfirmed by titration with perbenzoic acid or bromine solution. The yield is more than 5 90% of the theoretical. By oxidizing this mixture with perbenzoic acid and treating this reaction product, which contains an oxide, with dilute aqueous or alcoholic acids or alkali or other compounds, rearranging oxides like zinc chloride 10 or concentrated acids, for instance, 80% phosphoric acid, a mixture of substances is obtained from which ketonic reagents, like semicarbazide salts, precipitate the 3-methoxy-transandrosterone (17) in the form of a condensate from which the free B-methoxy-trans-androsterone (17) is obtained by known methods. The crystals have a double melting point: 42 and 73 C. This product is identical with the substance obtained 6 from the methyl ether or dihydrocholesterol with chromic acid according to Ruzickas known method. From it by hydrolysis of the methoxy group the trans-androsterone can be obtained. In place of the ether, employed above, other ethers may be used, such as methoxymethyl ether, dinitrophenyl ether and others.

Example 3 20 g. of bis-cholesteryl ether (M. P. 190 C.) are heated to gentle boiling, the temperature not exceeding 400". A volatile substance is distilled ofi which, on cooling, condenses to a light fluid. By re-distilling, this fluid is found to consist of a mixture of iso-octane and iso-octene. The residue, which is obtained in about theoretical yield, crystallizes from alcohol or other solvents, the crystals melting non-sharply at 160-170" C. This substance is dissolved in acetic acid and a soluaion of peractive acid is added which is prepared in the usual way and contains the equivalent of 110% of the theory for the addition of one oxygen atom to one double bond. The reaction mixture is kept at 0 for 24 hours, only the theoretical amount for one double bond being absorbed. The reaction mixture is poured into water, shaken out with ether and washed thoroughly to remove the surplus of reagent. The ether is dried and evaporated, the residue taken up with 10 times its amount of an alcoholic solution of hydrochloric acid containing 5% HO]. This mixture is boiled for live hours, then diluted with water and extracted with ether, the ether washed with water to remove the alcohol and with soda to remove the acid. The ether solution is evaporated and dried. The residue is now taken up with 10 times its amount of alcohol, a solution of semicarbazide acetate in alcohol added and the mixture boiled for 2 hours. The solid substance which is precipitated consists of the seml-carbazide of the bis-dehydroandrosterone ether. It is split with an alcoholic solution of oxalic acid, whereby the bis-dehydroandrosterone ether is obtained as a solid which after recrystallization melts at about 225. By boiling with hydrochloric acid this ether is easily split and yields dehydroandrosterone.

Example 4 7 among other compounds 3-hydroxy-androstane and the corresponding androstene, which are isolated from the mixture by crystallization from acetone, whereby the more soluble cracked compounds remain in solution, while the unchanged starting material crystallizes out.

Example 5 I 10 g. ofcholestanone are heated with an equal amount of a high boiling hydrocarbon like phenanthrene for 15 hours at approximately the boiling point of the mixture. With the phenanthrene, the iso-octane mixture distils off. By crystallization from methyl alcohol, the phenanthrene and 3-keto androstene are separated from the residue. In place of cholestanone, cholestanone dichloride and other substitution products can be used.

From the above it will be seen that we have provided a process whereby cyclopentano-phenanthrene compounds, of saturated orunsaturated nature, having an aliphatic side chain in the molecule are cracked at such side chain, yielding compounds which may be treated to yield therapeutically valuable substances, as by being oxidizedto compounds of the androsterone group.

It 'will be understood that variations in the specific procedures disclosed may be resorted to within the scope of the appended claims without departing from the spirit of the invention. Thus, other known methods of oxidation and other known ketone reagents for effecting separation of ketonic substances than those disclosed may be employed, or the reaction product may be isolated in any other known manner.

We claim:

1. The method of producing therapeutically valuable substances, which comprises heating a cyclopentano-polyhydro-phenanthrene compound having a hydrocarbon side chain of a plurality of carbon atoms in the 17-position, at temperatures at which one or more carbon compounds whose carbon atoms originate in such side chain are split ofi but at which the cyclopentanopolyhydro-phenanthrene nucleus remains intact,

and then oxidizing the residual compound to join one or more oxygen atoms to the cyclopentanopolyhydro-phenanthrene nucleus.

2. The method of producing therapeutically valuable substances, which comprises heating a cyclopentano-phena-nthrene compound having a hydrocarbon side chain of a plurality of carbon atoms in the l7-position, at temperatures at which the side chain is split off, but at which the cyclopentano-phenanthrene nucleus remains intact, subjecting the residue to the action of an.

oxidizing agent which joins one or more oxygen atoms to the nucleus, treating the reaction product with an agent capable of efiecting molecular rearrangement of the oxide so produced tothe ketonic form, reacting the ketone-containing mixture with a ketone reagent, separating the ketonic reaction product, and hydrolyzing the latter to liberate the ketone.

3. The method of producing degradation products having the cyclopentano polyhydro phenanthrene structure, which comprises heating a cyclopentano polyhydro phenanthrene compound having a hydrocarbon side chain of aplurality of carbon atoms joined to the nucleus in the l'l-position, to a cracking temperature at which a compound of a plurality of carbon atoms originating in such side chain is split off but at which the cyclopentano phenanthrene nucleus remains intact.

which the cyclopentano phenanthrene nucleus re-' mains intact.

5. The method of producing degradation products having the cyclopentano-polyhydro-phenanthrene structure, which comprises heating anompound of the general formula wherein R is a group containing the cyclopentano-polyhydro-phenanthrene structure; R1 is in the 3-position and is a member of the group consisting of H, HH, 0, OH,

and a group which on hydrolysis is converted into a hydroxyl group, the compound being unsaturated in the first ring when R is H or OH, and R2 is in the l'l-position and includes an aliphatic hydrocarbon side chain of a plurality of carbon atoms to a cracking temperature at which a compound of a plurality of carbon atoms originating in such side chain is split oil but at which the cyclopentano phenanthrene structure remains intact.

6. The method of producing degradation products having the cyclopentano polyhydro phenanthrene structure, which comprises heating a compound of the general formula wherein R is a group containing the cyclopentano polyhydro phenanthrene structure, R1 is in the 3- position and is a member of the group consisting of H, HH, 0, OH,

wherein R is a group containing the cyclopentano-polyhydro-phenanthrene structure, R1 is in the 3-position and is a member of the group consisting of H, HH, 0, OH,

and a. group which on hydrolysis is converted into a hydroxyl group, the compound being unsaturated in the first ring when R is H or OH, and R2 is in the 1'7-position and is the group CH(CH3) (CI-I2): CH (CH3)2, at temperatures at which the R: group is split off but pentano@olyhydro-phenanthrene structure 'remains intact, and then oxidizing the product to the cyclopentano-phenanthrene structure remains intact.

9. The method of producing cyclopentano polyhydro phenanthrene compounds which comprises subjecting a compound of the group consisting of cholestene and cholestane and derivatives thereof having in the 3-D0sition a substituent oi the class consisting of hydroxyl and groups which on hydrolysis are replaced by hydroxyl, to a cracking temperature at which the aliphatic side chain is split off, while the cyclopentano phenanthrene carbon structure remains intact.

10. The method according to claim 1, wherein the heating takes place at a. temperature of 280-400 C.

11. The method according to claim 1, wherein the heating takes place in the presence of an inert solvent whose boiling point is not substantially lower than the temperature at which the side chain is split 01!.

12. The method according to claim 1, wherein the heating takes place in the presence of a metal chloride cracking catalyst.

13. The method of producing oxygenated cyclopentano phenanthrene compounds which comprises subjecting a cyclopentano polyhydro phenanthrene compound, wherein the cyclopentano ring is unsubstituted and purely hydrocarbon in nature, to the action of an oxidizing agent capable oi introducing ketonic oxygen into the molecule.

14. The method of producing androstanedione which comprises heating cholestene at a temperature at which the aliphatic side chain is split oi! from the cyclopentano-polyhydro-phenanthrene nucleus but at which such nucleus remains intact, subjecting the product to an oxidizing treatment whereby oxygen is joined to the hydrocarbon nucleus, treating the reaction product with an agent capable of efiecting molecular rearrangement oi the oxide so produced to the ketonic form, reacting the mixture with semicarbazide, separating the disemicarbazide of androstanedione so obtained and splitting such compound to liberate freeandrostanedione.

15. The method of producing 3-methoxy-transandrosterone (17) which comprises heating dihydrocholesterol-methyl-ether at a temperature at which the side chain is split of! but at which the cyclopentano phenanthrene nucleus remains intact, separating the cyclopentano-polyhydrophenanthrene compound so obtained and oxidizing the same to introduce oxygen into the molecule, and then separating the ketonic reaction product by means of a ketone reagent and then splitting the resulting compound to liberate the free ketone.

16. Saturated and unsaturated 3-keto cycloproducing cyclopentano" 2,220,828 I at which the cyclopentano-polyhydro-phenanthrene compounds 01' the general structural formula.

om' cm 17. Saturated and phenanthrene compounds of the general structural formula CH: CH:

18. A cyclopentano-phenanthrene compound obtained by splitting oil the aliphatic side chain from a compound of the group consisting of cholestene, tetrahydrostigmasterol, dihydrositosterol, dihydrocholesterol, tetrahydroergosterol, coprosterol, epi-dihydrocholesterol, and their derivatives, including cholestanone, cholestenone,

the organic and inorganic esters, ethers, and acetals, the cyclopentano group of said compound being unsubstituted and purely hydrocarbon in nature.

19. Dimethyl cyclopentano polyhydro phenanthrene compounds free of aliphatic side chains in the cyclopentano ring and containing a substituting group in the first ring which on hydrolysis is replaceable by an OH group, the cyclopentano ring beingpurely hydrocarbon in nature.

20. A 10,13-dimethyl cyclopentano-polyhydrophenanthrene compound wherein the cyclopentano ring is purely hydrocarbon in nature and is free of aliphatic side chains, the first ring being unsaturated.

21. A 10,13-dimethyl cyclopentano-polyhydrophena'nthrene compound in which the cyclopentano ring is purely hydrocarbon in nature and wherein the first ring contains a substituting group which on hydrolysis is replaceable by an OH group.

22. 3-methoxy cyclopentano polyhydro phenanthrene.

23. The method of producing therapeutically valuable substances which comprises subjecting a member of the, group consisting of cholestene, dihydrocholes terol, tetrahydrostigmasterol, dihydrositosterol, tetrahydroergosterol, coprosterol, epidihydrocholesterol, and their derivatives, including cholestanone, cholestenone, the organic and inorganic esters, ethers, and acetals, to a temperature at which the aliphatic side chain is split oil but at which the cyclopentano-phenanthrene structure remains intact, oxidizing the cyclopentano-phenanthrene compound so obtained, treating the reaction product with an agent capable of effecting molecular rearrangement of the resulting oxide to the ketone form, and separating the ketonic product.

24. The method of producing therapeutically valuable substances which comprises subjecting a cholesterol compound to an elevated temperature at which the aliphatic side chain s split off but at which the cyclopentano-phenanthrene structure remains intact, oxidizing the product so obunsaturated cyclopentano tained, treating the reaction product with an agent capable of effecting molecular rearrangement of the resulting oxide to the ketonic form,

and separating the ketonic product.

25. The method according to claim 3, wherein the heating takes place at temperatures above 280C.

26. The method according to claim 3, wherein the heating takes place in the presence of an inert m solvent whose boiling point is not substantially lower than the temperature at which theside chain is split off.

2'7. A 10,13-dimethyl cyclopentano polyhydro phenanthrene compound wherein the cyclopentano ring is purely hydrocarbon in nature and is free of aliphatic side chains, an oxygen-containing group being located at the 3-carbon.

'ERWIN SCI-IWENK. 

